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Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer
- Source :
- The Laryngoscope. 126:E156-E163
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
Abstract
- Objectives/Hypothesis Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti-EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3-kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC. Study Design Preclinical in vivo study. Methods We evaluated the anti-tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice. Results As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association. Conclusion In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways. Level of Evidence N/A. Laryngoscope, 126:E156–E163, 2016
- Subjects :
- 0301 basic medicine
Oncology
medicine.medical_specialty
Cetuximab
business.industry
medicine.disease
Head and neck squamous-cell carcinoma
Temsirolimus
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Otorhinolaryngology
Tumor progression
030220 oncology & carcinogenesis
Internal medicine
Sirolimus
medicine
Cancer research
business
Protein kinase B
PI3K/AKT/mTOR pathway
medicine.drug
EGFR inhibitors
Subjects
Details
- ISSN :
- 0023852X
- Volume :
- 126
- Database :
- OpenAIRE
- Journal :
- The Laryngoscope
- Accession number :
- edsair.doi...........3079c3d3d2c4eefde2c7a79f1086e70c